Deciphering the role of human thiol systems (Trx/Grx) in the transcriptional regulation: An emphasis on the role of thiol enzymes with the multifunctional APE1/Ref-1 enzyme in human health and diseases.

A thiol-dependent redox system exists in mammalian cells, which plays a critical role in maintaining the redox balance and protecting against oxidative damage. Thiol-containing proteins, which include glutaredoxin (Grx) and thioredoxin (Trx), are involved in redox regulation in mitochondria, as well as redox activation of transcription factors (TFs) by thiol-disulfide exchange. It has been reported that Trx can enhance the redox activity of apurinic/apyrimidinic endonuclease 1 (APE1), an important multifunctional DNA repair enzyme involved in the base excision repair (BER) pathway, which is responsible for repairing damaged oxidative DNA bases and also regulates the redox status of several TFs via its redox active Cys residues and is named redox effector factor 1 (Ref-1). Grx and Trx are involved in redox activation of APE1/Ref-1 and also activate TFs such as AP-1, Nrf-2, NF-κB, STAT3, CREB, PAX-8, and HIF-1α by mediating the reduction of the thiol group. Phytochemicals, with strong antioxidant properties, exhibit neuroprotective potential against neuronal oxidative stress by targeting Grx and Trx. The focus and novelty of the present article are to emphasize and illustrate key molecular mechanisms involved in the redox regulation of several TFs, as well as their potential biological roles in human disease. Lastly, the beneficial/modulatory roles of the thiol system by different phytochemicals provide a new avenue for improving cellular health and reversing disease, as discussed in the context of human cancer, cardiovascular disorders (CVDs), and neurodegenerative disease like AD.